Steroids are used extensively in the treatment of human disease processes. One of the most common classes of steroids are those compounds known as conjugated estrogens. Peri-menopausal, menopausal and post-menopausal women frequently experience a large variety of conditions and disorders related to the decrease of estrogen levels in the body. The decrease in estrogen levels is primarily responsible for hot flashes, vaginal atrophy, osteoporosis (Garraway et al, Mayo Clinic Proceedings, 54, 701-707, (1979)) and the loss of protection against heart attacks in women (Havlik, R. J. and Manning-Feinleid, P. H. 1979, NIH Publication No. 79-1610, U.S. Department of HEW).
It is generally known that estrogen replacement therapy is the most effective method for the treatment of menopausal hot flashes and vaginal atrophy. It is also effective in retarding or preventing osteoporosis. A number of therapeutic regimes for estrogen replacement therapy are known. Plunkett and Wolfe (U.S. Pat. No. 4,826,831) disclose a method of hormonally treating menopausal disorders in women. The administrative regimen comprises the continuous and uninterrupted administration of a progestogen to a woman while cyclically administering an estrogen by using a repetitive dosage regimen. The regimen calls for administering the estrogen continuously for a period of time between about 20 and 120 days, followed by terminating the administration of the estrogen for a period of time between about 3 and 7 days.
The estrogens used in the present disclosure may be those which are orally active and are selected from the group of natural estrogens such as equilin, estrone, 17-.alpha.-dihydroequilin, 17-.beta.-dihydroequilin and 17-.alpha.-estradiol and their corresponding sulfate esters.
The progestogens useful in this invention are selected from the group comprising medroxyprogesterone acetate, medroxyprogesterone, norethindrone, and progesterone. Other progestogens include, but are not limited to, norethindrone acetate, ethynodiol diacetate, dydrogesterone, norethynodrel, allyl estrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, dl-norgestrel, levo-norgestrel and megestrol acetate.
The present invention provides a novel pharmaceutical composition using low dose estrogens alone or in combination with a progestogen in a continuous uninterrupted fashion where the frequency of administration is at least once daily. The term "continuous" as applied in the specification means that the dosage is administered at least once daily. The term "uninterrupted" means that there is no break in the treatment, and that the treatment is administered at least once daily in perpetuity until the entire treatment is ended.
The carrier base material used in the invention comprises a hydroxyalkyl cellulose and/or a hydroxyalkyl alkylcellulose. The hydroxyalkyl cellulose and/or the hydroxyalkyl alkylcellulose employed in the present invention is exemplified by hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylethylcellulose, hydroxybutylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxyethylethylcellulose, hydroxyethylmethylcellulose, and mixtures thereof.
Hydroxypropylmethylcelluloses are commercially available in various grades as described by Schor, et al. (U.S. Pat. No. 4,369,172). Commercial designations of the various hydroxypropylmethylcelluloses are based on the viscosities of 2% aqueous solutions at 20.degree. C. The viscosities range from 15 cps to 30,000 cps and represent number average molecular weights (Mn) ranging from about 10,000 to over 150,000.
Christenson and Dale (U.S. Pat. No. 3,065,143) disclose the use of certain hydrophilic gums, including hydroxypropylmethylcelluloses, in the preparation of "sustained release" formulations. The tablet disclosed consisted essentially of a drug mixed with a hydrophilic mucilaginous gum which swells when hydrated forming a "soft mucilaginous gel barrier" on the surface of the tablets when brought into contact with the aqueous fluids of the gastrointestinal tract.
The ability to form a mucilaginous gel barrier is dependent upon the molecular weight of the hydrophilic gum. The need to use high molecular weight hydroxypropylmethylcelluloses for this purpose is evident from the specification of U.S. Pat. No. 3,065,143. Other hydrophilic gums having high molecular weights such as sodium carboxymethylcellulose and carboxypolymethylene are effective hydrophilic gums.
Schor, et al. (U.S. Pat. No. 4,369,172) describes the use of a carrier base material combined with a therapeutically active medicament which is shaped and compressed to a solid unit dosage form having a regular and prolonged release pattern upon administration. The carrier base is comprised of hydroxypropylmethylcellulose or a mixture of hydroxypropylmethylcellulose and up to 30% by weight of the mixture of ethylcellulose and/or up to 30% by weight of the mixture of sodium carboxymethylcellulose. The hydroxypropylmethylcellulose has a hydroxypropoxyl content of 9-12 weight percent and a number average molecular weight of less than 50,000. Notably, the formulations described do not form a soft mucilaginous gel. Also, the moisture content of the carrier consisting of: (1) the hydroxypropylmethylcellulose having a hydroxypropoxyl content of 9-12 weight percent, having (2) a number average molecular weight of below 50,000 and, (3) the medicament and other ingredients, if any, has little or no influence on the sustained release characteristics. Further, the moisture content of the finished dosage form plays a minor role as compared to chemical structure of the carrier on the rate of release of the medicaments. The medicaments disclosed do not include conjugated estrogens. Therefore, the sustained release of medicaments depends on the chemical structure of the carrier and is not dependent on the formulation of a soft mucilaginous gel barrier on the surface of the tablet as disclosed in U.S. Pat. No. 3,065,143 or the moisture content of the tablet.
Schor et al. (U.S. Pat. No. 4,389,393) also describes the use of a carrier base material combined with a therapeutically active medicament which is shaped and compressed to a solid unit dosage form having a regular and prolonged release pattern upon administration. The carrier base is comprised of material being one or more hydroxypropyl methylcelluloses or a mixture of one or more hydroxypropyl methylcelluloses and up to 30% by weight of the mixture of methylcellulose, sodium carboxymethylcellulose and/or other cellulose ethers, and wherein at least one of the hydroxypropyl methylcelluloses has a methoxy content of 16-24 weight %, a hydroxypropoxyl content of 4-32 weight percent and a number average molecular weight of at least 50,000. Notably, the carrier base material constitutes less than about one third of the weight of the solid unit dosage form. Thus, an object of U.S. Pat. No. 4,389,393 is to provide a carrier base which comprises less than about one third of the weight of the solid unit dosage form. Additionally, the moisture content of the finished dosage form has little or no influence on the sustained release characteristics and plays a minor role as compared to the chemical structure of the carrier and its concentration on the rate of release of medicaments. The medicaments disclosed in U.S. Pat. No. 4,389,393 do not include conjugated estrogens.
Dopper et al. (U.S. Pat. No. 5,395,627) discloses a process for the preparation of a granule comprising (a) a carrier comprising a diluent and binder and (b) a film coating the carrier wherein the film comprises desogestrel and a lubricant. The stability of the finished granulate is not dependent on its moisture content. Further, the medicaments disclosed in U.S. Pat. No. 5,395,627 do not include conjugated estrogens.
In sharp contrast to the aforementioned patents, the formulations described herein are dependent on the formation of a soft, mucilaginous gel for optimum controlled release of the conjugated estrogens. Furthermore, the stability of the formulations described herein are dependent upon the moisture content of the finished dosage form.